Despite expanding control efforts, malaria still claims >1 million lives each year. A malaria vaccine is urgently needed, but progress toward this goal has been hindered by our limited understanding of the mechanisms underlying immunity to malaria and a lack of reliable in vitro correlates of protection. Recently, experimental challenge models employing sporozoite vaccination have shed light on host defense mechanisms important for protective immunity, highlighting a critical role for malaria-specific T cells. These intriguing results suggest that careful study of the T cell response to malaria in cohorts of individuals with varying degrees of immunity may offer insight into the immune mechanisms required for protection, providing guidance for the rational design of vaccines. However, it is not known whether the mechanisms responsible for vaccine-induced immunity are identical to those underlying naturally acquired immunity. To date, population-based studies of antimalarial immunity among naturally exposed individuals have yielded no clear and consistent immune correlates of protection, but such efforts have been hindered by suboptimal measures of malaria incidence as well as the inability to control for confounding by exposure intensity and age. Using samples and data collected through an ongoing ICEMR cohort study, we have a unique opportunity to perform detailed analyses of malaria-specific T cell responses in a large cohort of children who will be followed longitudinally with careful measures of both malaria incidence and household-level exposure intensity. This cohort is based in a region of Uganda with exceptionally high year-round transmission intensity, and includes children 6 mos to 10 yrs of age, spanning the developmental period during which the natural acquisition of clinical immunity is normally observed. The proposed studies will utilize multiparameter flow cytometry, gene expression microarrays, and multiplex cytokine analysis to characterize the immune response to malaria and determine the relationship between this response and malaria incidence, controlling for both age and household-level exposure intensity. These studies will greatly enhance our understanding of the acquisition of natural immunity to malaria during childhood and the immune mechanisms responsible for protection.